The development of pharmacotherapies for the treatment of cocaine dependence has been a high priority in addiction research for more than three decades, yet no medication has been approved in the USA or in other countries for this disease. The absence of efficacious treatments remains a significant problem since, for example, the National Survey on Drug Use and Health statistics from 2010 show that approximately 1.5 million individuals were current cocaine users. Cocaine use is also associated with significant medical and psychiatric morbidity. It has been estimated that over 500,000 drug misuse or abuse visits were the result of recent cocaine exposure. In view of the misuse and a lack of treatment for cocaine addiction we have sought an alternative treatment strategy that targets the drug itself aiming to keep drug below its effective concentration rather than try to modulate or disrupt the effects of the drug at sites of action in the brain. We have termed this strategy immunopharmacotherapy. The current proposal has been tailored to investigate immunopharmacotherapy from two vantage points; the first will explore antibody manifolds as an approach to attenuate cocaine toxicity while the second will examine active vaccination as a means to curb cocaine abuse. Based on this general semblance we have crafted a set of specific aims including: (1) Implementing a domain deleted recombinant fragment (scFv-Fc) design to understand antibody manifold requirements for the treatment of immediate as well as long-term cocaine toxicity effects. (2) How hapten, carrier and adjuvant formulations impact a vaccines performance. A systematic study will be conducted wherein each of these three components will be varied. A vaccine's success will be graded based upon antibody-cocaine affinity/total antibody produced as well as kinetic parameters defining the degradation of cocaine. (3) To engage endogenous antibodies as a means to overcome the weak immunogenicity of drug of abuse vaccines. The underlying principle to a successful vaccine is a potent immune response. This has also been an Achilles heel as drug-immune responses have been widely variable. Anti-Gal is the most abundant natural antibody in humans; a vaccine expressing ?-epitopes that can be targeted to antigen presenting cells (APCs) would readily increase the immunogenicity of the vaccine. We will exploit ?-Gal to target our cocaine haptens to APCs for a superior vaccine. (4) A metric to test our most promising active cocaine vaccine formulations will be conducted in a rodent model examining cocaine dependence and re-escalation. The importance of this model is that trying to break physical dependence through re-escalation studies is extraordinarily difficult to disrupt by any medications mean and will pose a real test to our vaccine development. The research we have planned both highlight the promise of immunopharmacotherapy and will also strive to overcome the deficiencies of this approach in our quest for developing vaccines for the treatment of cocaine abuse and its toxicity.